Copyright © 2007, European Society of Cardiology
The acute phase protein 
2-macroglobulin induces rat ventricular cardiomyocyte hypertrophy via ERK1,2 and PI3-kinase/Akt pathways*
aDepartment of Physiology, Justus-Liebig-University Giessen, Aulweg 129, 35392 Giessen, Germany
bDepartment of Cell Biology, GKSS Research Institute Teltow, Germany
cClinic of Internal Medicine I, Friedrich Schiller University Jena, Germany
* Corresponding author. Tel.: +49 641 9947333; fax: +49 641 9947219. heinrich.sauer{at}physiologie.med.uni-giessen.de
Objective 
2-macroglobulin (2M) is an acute phase protein released to the serum upon challenges such as cardiac hypertrophy and infarction. Here we report on the role of 2M in the induction of hypertrophic cell growth, contractile responsiveness of rat ventricular cardiomyocytes, and on the underlying extracellular regulated kinase 1,2 (ERK1,2) and phosphoinositide 3-kinase (PI3-kinase)/Akt pathways.
Methods Cell volume and cross-sectional areas were assessed as parameters of hypertrophic growth, and real time RT-PCR for the analysis of hypertrophy-related genes was performed. Protein synthesis was analyzed by 14C-phenylalanine incorporation. Activation of ERK1,2, PI3-kinase and Akt was assessed by immunohistochemical analysis of phosphorylated proteins. Contractile responsiveness was investigated by determination of cell shortening following electrical field stimulation. Intracellular calcium concentration [Ca2+]i was determined by fluo-3 microfluorometry.
Results Treatment of ventricular cardiomyocytes for 24 h with 2M significantly increased cell volume and protein synthesis as well as expression of hypertrophy-associated genes [brain natriuretic protein (BNP), β-myosin heavy chain (β-MHC), myosin light chain-2 (MLC-2), atrial natriuretic factor (ANF), and skeletal -actin]. Comparable effects were achieved by treatment of cells with an antibody directed against the 2M-receptor LDL receptor-related protein-1 (LRP-1) and counteracted upon coincubation with receptor-associated protein (RAP), suggesting an involvement of 2M-LRP-1 signalling. Furthermore, 2M treatment increased sarcoplasmic reticulum Ca2+-ATPase (SERCA-2a) expression, diastolic and systolic [Ca2+]i, and contractile responsiveness after electrical stimulation. Shortly after 2M stimulation, activation of ERK1,2, Akt, and PI3-kinase pathways was observed. Consequently, 2M-induced protein synthesis was inhibited upon treatment with the ERK1,2 inhibitor UO126 as well as by LY294002 and wortmannin, which inhibit PI3-kinase, and by rapamycin, which inhibits mammalian target of rapamycin (mTOR) downstream of Akt.
Conclusions Our data show that 2M induces hypertrophic cell growth in rat ventricular cardiomyocytes via ERK1,2 and PI3-kinase/Akt and improves cardiac cell function.
KEYWORDS Cardiac hypertrophy; Acute phase proteins; 2-macroglobulin; SERCA
* Gerd Heusch (Universitätsklinikum Essen, Essen, Germany) served as Guest Editor for this article.
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